Noninvasive high-frequency oscillation ventilation as post- extubation respiratory support in neonates: Systematic review and meta-analysis

Introduction Noninvasive High-Frequency Oscillatory Ventilation (NHFOV) is increasingly being adopted to reduce the need for invasive ventilation after extubation. Objectives To evaluate the benefits and harms of NHFOV as post-extubation respiratory support in newborns compared to other non‐invasive respiratory support modes. Material & methods We included randomized controlled trials comparing NHFOV with other non-invasive modes post-extubation in newborns. Data sources were MEDLINE (via Pubmed), Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, WHO international clinical trials registry platform and Clinical Trial Registry, forward and backward citation search. Methodological quality of studies was assessed by Cochrane’s Risk of Bias tool 1.0. Results This systematic review included 21 studies and 3294 participants, the majority of whom were preterm. NHFOV compared to nasal continuous positive airway pressure (NCPAP) reduced reintubation within seven days (RR 0.34, 95% CI 0.22 to 0.53) after extubation. It also reduced extubation failure (RR 0.39, 95% CI 0.30 to 0.51) and reintubation within 72 hrs (RR 0.40, 95% CI 0.31 to 0.53), bronchopulmonary dysplasia (RR 0.59, 95% CI 0.37 to 0.94) and pulmonary air leak (RR 0.46, 95% CI 0.27 to 0.79) compared to NCPAP. The rate of reintubation within seven days (RR 0.62, 95% CI 0.18 to 2.14) was similar whereas extubation failure (RR 0.65, 95% CI 0.50 to 0.83) and reintubation (RR 0.68, 95% CI 0.52 to 0.89) within 72 hrs were lower in NHFOV group compared to nasal intermittent positive pressure ventilation. There was no effect on other outcomes. Overall quality of the evidence was low to very low in both comparisons. Conclusions NHFOV may reduce the rate of reintubation and extubation failure post-extubation without increasing complications. Majority of the trials were exclusively done in preterm neonates. Further research with high methodological quality is warranted.

extubation failure (RR 0.65, 95% CI 0.50 to 0.83) and reintubation (RR 0.68, 95% CI 0.52 to 0.89) within 72 hrs were lower in NHFOV group compared to nasal intermittent positive pressure ventilation.There was no effect on other outcomes.Overall quality of the evidence was low to very low in both comparisons.

Conclusions
NHFOV may reduce the rate of reintubation and extubation failure post-extubation without increasing complications.Majority of the trials were exclusively done in preterm neonates.Further research with high methodological quality is warranted.

Background
The use of invasive mechanical ventilation (IMV) in neonates with severe respiratory disease may lead to complications such as air leaks, bronchopulmonary dysplasia (BPD), and impaired neurodevelopmental outcomes.This has prompted a strategy of early weaning and extubation.
Post-extubation strategies like non-invasive respiratory support (NRS) are employed to minimize reintubation and reduce extubation failure rates.Nevertheless, neonates may still require reintubation, which is an independent risk factor for increased mortality and morbidity [1].
High failure rates of nasal continuous positive airway pressure (NCPAP) as post-extubation NRS have led to the search for more effective non-invasive options.Nasal intermittent positive pressure ventilation (NIPPV) has shown promise in reducing extubation failure rates compared to NCPAP.NIPPV reduces chronic lung disease slightly although it has little impact on mortality compared to NCPAP [2].
Non-invasive high-frequency oscillatory ventilation (NHFOV) is a newer approach that combines the advantages of high-frequency oscillatory ventilation (HFOV) and nasal CPAP.NHFOV offers physiological advantages, including an increase in functional residual capacity leading to improved oxygenation, elimination of the need for synchronization, and efficient CO2 removal [3,4].
The adoption of NHFOV is on the rise and is becoming more prevalent in neonatal intensive care units (NICUs) [5].In a meta-analysis, neonates with respiratory distress syndrome had fewer intubations when using NHFOV as the primary respiratory support [6].Systematic reviews suggest that NHFOV and NIPPV are more effective than CPAP in reducing neonatal morbidities [7,8].
Previous systematic reviews that examined the efficacy of NHFOV as post-extubation respiratory support were focused on preterm neonates and suggested that NHFOV may lower the need for reintubation after extubation in mechanically ventilated newborns without notable adverse effects [9,10].However, the quality of evidence was found to be low to very low.Metaanalyses compared NHFOV only against NIPPV and CPAP for post-extubation respiratory support and only one among them compared NHFOV and CPAP.Furthermore, none of the previous meta-analyses examined the efficacy of NHFOV on the need for escalation to other NRS methods post-extubation.The effectiveness of NHFOV in term neonates for post-extubation respiratory support still remains uncertain.In light of the current gaps in knowledge, the objective of the present study was to conduct an exploratory review to synthesize all available evidence on the use of NHFOV in neonates.

Objective
To evaluate the benefits and harms of NHFOV as post-extubation respiratory support in newborns compared to other forms of non-invasive respiratory support.

Methods
This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline [11] and was registered in PROSPERO (CRD42022374609).

Study selection
Inclusion criteria.All included studies fulfilled the following criteria: Type of studies.Randomised, quasi-randomised and cluster randomised trials that evaluated at least one of the prespecified outcomes.
Type of population.Neonates of all gestation extubated to an NRS from invasive mechanical ventilation.
Type of intervention.The trials that compared NHFOV with any other form of NRS post-extubation.Eligible control interventions: NCPAP, NIPPV, synchronized NIPPV (SNIPPV), non-Invasive Ventilation-Neurally Adjusted Ventilatory Assist (NIV-NAVA), heated humidified high flow nasal cannula (HHHFNC), oxygen/or no treatment.Any interface or device used to deliver NRS was included.f.Nasal injury.
i. Length of hospital stay (LOS).j.Retinopathy of prematurity (ROP) (any and severe-stage �3) as per the International Committee for the Classification of Retinopathy of Prematurity classification [13].

Exclusion criteria
The exclusion criteria were as follows: 1. Observational studies, reviews, cross-over trial 2. Overlapping study

Study selection
After deduplication, two independent reviewers screened the titles and abstracts of all records retrieved and excluded studies unrelated to our topic.Next, two researchers independently assessed the full-text articles of the selected records for their eligibility according to inclusion and exclusion criteria described above.Disagreements were resolved by discussion or by a third reviewer.Author names, trial registration numbers, study locations, dates and sample characteristics were used to recognize multiple reports originating from the same study S1 Appendix.

Assessment of methodological quality
We assessed risk of bias in the included studies using the Cochrane Collaboration 'Risk of bias' tool for randomised trials (RoB 1.0) [14].The following domains were assessed-selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias.Two review authors independently assessed the RoB.Disagreements were sorted out by discussion or by consulting the third reviewer S1 Appendix.

Quality of evidence
We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [15] to assess the quality of evidence for the following seven clinically relevant outcomes:

Statistical analysis and data synthesis
The data analysis was conducted using Review Manager version 5.4.1 with a fixed-effect model.A random-effects model was employed when heterogeneity (I 2 ) exceeded 50%.Risk Ratio (RR) was used for dichotomous outcomes, the standardized mean difference (SMD) for continuous data, and 95% confidence intervals (CI) were reported.For hospital stay duration reported as median and interquartile ranges, the mean was estimated using methods proposed by Wang et al. [16].We analysed data on an intention-to-treat basis.We analysed data on alltrial level and separately for preterm subgroup.However, for BPD, ROP and IVH, data for only preterm neonates were pooled for primary analysis.The Number Needed to Treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH) was calculated for statistically significant results.Leave-one-out meta-analysis was done in RStudio version 4.2.1.

Characteristics of included studies
Seventeen studies were from China [18, 21, 24, 26-37, 42, 43] and there was one each from Thailand [20], India [23], Germany [25] and Egypt [41].Only one study was multicentric [18].Additionally, twelve papers were exclusively available in the Chinese language and were translated into English using Google Translate [28-37, 42, 43].There was one more article in Chinese with an available English translation [27].We provided details in the Characteristics of included studies Tables 1-3.

Device and ventilator strategies
We found studies that compared NHFOV with NCPAP and NIPPV.Included studies used variable or continuous flow devices to deliver CPAP [18, 21, 24-26, 31, 32, 37].Some studies did not mention the type of CPAP used [33][34][35][36].Single trial exclusively compared synchronized NIPPV with NHFOV [20].The largest trial by Zhu et al. [18] used only non-synchronized NIPPV.The information on synchronization was unavailable in other trials.Various ventilators were used to deliver NHFOV.Prespecified criteria for extubation failure were not reported in three trials [28,42,43].Additionally, some studies did not mention the intervention carried out in case of NRS failure following extubation [27,28,33,42,43].The definition of some secondary outcomes was not clear.The antenatal steroid coverage ranged from 32.2% to 93.5%.

RoB
All included studies had high RoB for performance bias.Secondary outcomes.All-trials analysis showed statistically significant reduction in extubation failure within 72 hours post-extubation (RR 0.39, 95% CI 0.30 to 0.51; participants = 1404; studies = 7; I 2 = 0%) in neonates extubated to NHFOV (Fig 3).The NNT for successful treatment was 6.8(95% CI 5.4 to 9.2).Two studies [25,43] reported extubation failure at 7 days and one of them reported data for both 72 hours and 7 days.Two RCTs that reported extubation failure at 7 days found no significant difference (S3 Fig).
One trial reported extubation failure rate but the trial did not specify the type of rescue treatment or intervention that was employed in the event of extubation failure [27].One study reported extubation failure within 72 hrs and reintubation within 7 days [25].All other trials employed reintubation after the failure of extubation within 72 hrs.A meta-analysis of RCTs that reported reintubation within 72 hrs (RR 0.40, 95% CI 0.31 to 0.53; participants = 1329; studies = 5; I 2 = 0%) also found statistically significant reduction.

Quality of the evidence
The overall quality of evidence as per GRADE is provided in the Summary of Findings tables (S3 and S4 Tables).Lack of blinding to outcome assessor was not considered a source of bias

Subgroup analysis and sensitivity analysis
Meta-analysis restricted to preterm neonates.Separate meta-analyses for other outcomes by restricting the analyses to preterm neonates (<37 weeks gestation) revealed no change in the pattern of results for both comparisons (S8 and S9 Figs).The effect estimates are summarized in S5 and S6 Tables.
Comparison of NHFOV with NCPAP and NIPPV in term neonates.Meta-analysis including only term neonates was not possible for any of the outcomes due to insufficient data.Only one study [27] exclusively included term neonates.Lou et al. [27] reported reduced extubation failure rate (11.43%, vs 35.29%,P<0.05) and nasal injury (5.71% vs 32.35%) in NHFOV group compared to NCPAP.The rate of pulmonary air leak was similar in both groups.
Subgroup analysis for RoB.For sensitivity analysis, we divided studies into two subgroups on the basis of RoB: (i) low-risk-of-bias trials-studies that had low or unclear risk of bias only in blinding of outcome assessors (in addition to high risk of bias in blinding of participants and personnel).(ii) high-risk-of-bias trials-studies that, in addition, had unclear or high risk of bias in one or more of the other domains for risk of bias.Subgroup analysis was not possible for all outcomes.The overall results did not change significantly in low-risk-ofbias trials for any outcome except for pulmonary air leak (NHFOV vs NCPAP) and extubation failure (NHFOV vs NIPPV).
NHFOV vs NCPAP.Low-risk-of-bias trials showed no difference whereas high-risk-of-bias subgroup showed a significant difference in the incidence of pulmonary air leak in favour of NHFOV (S7 Table ).
NHFOV vs NIPPV.Low-risk-of-bias trials showed no reduction whereas high-risk-of-bias trials showed a significant reduction in extubation failure rate in NHFOV group (S8 Table ).
Addressing heterogeneity and leave-one-out meta-analysis.NHFOV vs NCPAP.There was unexplained moderate to high heterogeneity in BPD, nasal injury and LOS.We drew Baujat plot which detected influential studies contributing to heterogeneity (S10 Fig) .Leave-oneout meta-analysis revealed substantial reduction in heterogeneity and change in effect estimate after removing influential studies (S11 Fig) .Additionally, subgrouping by preterm and lowrisk-of-bias trials eliminated heterogeneity in LOS (I 2 = 0).
NHFOV vs NIPPV.Moderate heterogeneity was observed in reintubation within seven days and mortality before hospital discharge which may be explained by clinical heterogeneity.
Finally, we ran a "leave-one-out" sensitivity analysis, omitting one study at a time, to see if the findings were influenced by a single study.Leave-one-out meta-analysis revealed that the effect estimates for extubation failure remained stable in both comparisons (S12 Fig) .Some of the effect estimates substantially changed reflecting influential studies.
Publication bias.Visual inspection of funnel plot revealed asymmetry for LOS in comparison between NHFOV and NCPAP and for nasal injury in comparison between NHFOV and NIPPV (S13 Fig) .There was no evidence of funnel plot asymmetry for other outcomes in both comparisons.

Discussion
In this meta-analysis, we found that NHFOV reduced the incidence of reintubation at seven days compared to NCPAP but not NIPPV.However, extubation failure and reintubation within 72 hours were lower in the NHFOV group compared to both NCPAP and NIPPV.We found lower risk of BPD, pulmonary air leak and ROP of any stage and shorter LOS in NHFOV group compared to NCPAP.There was a trend towards lower BPD when NHFOV was compared to NIPPV.However, NHFOV did not significantly impact other outcomes.The estimates of effects were similar when including only preterm neonates.The overall quality of evidence was low to very low.
We conducted subgroup analysis to determine if the methodological quality of the included trials influenced the treatment effect estimates.In the subgroup of studies with low risk of bias, the effect estimates remained statistically significant for extubation failure within 72 hours, BPD and LOS and non-significant for mortality, nasal injury, and IVH grade �3 when comparing NHFOV and NCPAP.In comparison between NHFOV vs NIPPV, low-risk-of-bias trials showed no difference whereas high-risk-of-bias trials showed reduction in extubation failure.The results of other outcomes did not show significant change in RoB subgroup analysis.This suggests that the results for these outcomes were robust and consistent.Furthermore, we found that high-risk-of-bias trials overestimated the effect estimates for some secondary outcomes.Sufficient data were available only for preterm neonates to do subgroup meta-analysis.A significant proportion of the participants in the included studies were preterm neonates.As a result, the trial level subgroup analysis focusing on preterm neonates have not yielded a dramatic change in effect estimates.Leave one out meta-analysis revealed that some of the results were sensitive for removal of studies.Meta-analyses enhance statistical power and precision in determining the studied effect.However, excluding a single study is likely to alter the pooled effect estimate, sometimes in a significant manner particularly if there are only a few numbers of studies.
An association between reintubation within 72 hrs of extubation and increased likelihood of moderate-to-severe BPD or death in very low birth weight infants was reported [44] Here, we found that NHFOV probably reduces the risk of extubation failure or reintubation within 72 hrs in NICU patients when compared to NCPAP or NIPPV.The decreased rate of reintubation probably played a role in the lower occurrence of BPD in neonates receiving NHFOV.In addition to its effectiveness, our review demonstrated NHFOV's safety for newborns.

Strength
This review has multiple strengths such as an extensive search and a pre-registered protocol.We included 21 RCTs with a total of 3294 newborns.We included the most recently published RCTs and articles published in non-English language in our review.It incorporates substantial new data thus contributing to increased precision in estimating treatment effects.We analysed extubation failure and reintubation as distinct outcomes.Previous reviews focussed only on preterm neonates whereas we studied a broad research question and included neonates of all gestational ages.This allowed us to identify several RCTs which included term neonates or mixed population.We conducted subgroup and sensitivity analysis to determine the robustness of the results and explored heterogeneity.Our exploratory review highlights several evidence gaps for future research.We contacted authors of registered clinical trials that met our inclusion criteria to find additional results to include in this review.Furthermore, trials with methodologically good quality contributed to the majority of the data to the meta-analyses.

Limitations
Most of the included RCTs were conducted in developing countries, with a notable paucity of studies from developed countries.Most trials were small, single-centre studies and published from low-and middle-income countries.Caregivers cannot be blinded due to the nature of the interventions which may have led to bias.Majority of the population was preterm in our meta-analysis.We were unable to do meaningful subgroup analysis for full term, very preterm, and extremely preterm neonates due to limited data.There was limited information on the type of NCPAP or synchronization in NIPPV.Some studies lacked defined criteria for extubation failure and some secondary outcomes, and a few didn't specify interventions following NRS failure after extubation.No study reported mortality at 28 days of life.We didn't find any study that compared NHFOV with NIV-NAVA, HFNC or oxygen/no treatment.
The incidence of BPD was relatively high among neonates, regardless of the interventions studied.The antenatal steroid coverage was notably poor in majority of the trials.These specific characteristics could have impacted our findings.Furthermore, factors like equipment availability, costs to patients and the healthcare system, and the level of nursing care vary across health systems and regions that may potentially impact the efficacy of different NRS modes.Thus, the results might differ in populations with different characteristics or in settings with different expertise.Additionally, diverse ventilator settings and extubation failure criteria might also affect the efficacy of NRS.
Previous reviews also found reduction in reintubation rate when NHFOV was compared to NIPPV although these reviews included only preterm and fewer articles [9,10].Similarly, previous reviews did not show any effect on other outcomes when NHFOV was compared with NIPPV [9,10].A network meta-analysis showed reduction in reintubation rate within seven days of extubation with NHFOV compared to continuous flow CPAP but not when compared to variable flow CPAP or NIPPV [8].The largest trial by Zhu et al. [18] similarly showed a decrease in early reintubation in NHFOV group as compared to NCPAP groups.However, compared to NIPPV, this reduction did not achieve statistical significance.
Extubation failure has both prognostic and patient-related importance.Interventions that can reduce reintubation risk are valuable to a wide range of stakeholders involved in patient care and decision-making.The majority of the participants included in this review received non-synchronized NIPPV.As SNIPPV might result in better outcome, this mode needs to be compared with NHFOV in future trials.Future trials should include well-defined homogenous populations.Our results are mainly applicable to preterm neonates.There is paucity of research in term neonates and in conditions like BPD and MAS.Different nasal interfaces can impact the delivery of NHFOV and affect patient outcomes.Multi-center trials from developed countries with rigorous methodology are needed to further confirm the efficacy and safety of NHFOV.

Conclusion
Despite some limitations, in this meta-analysis NHFOV demonstrated reduction in reintubation following extubation when compared to NCPAP or NIPPV.Importantly, the use of NHFOV did not appear to increase the risk of serious complications.However, caution is warranted in interpreting the results due to the low to very low certainty of evidence.Further multi-center randomized controlled trials are warranted to confirm the effectiveness and safety of NHFOV as post-extubation respiratory support.

Outcomes 1 .
Primary outcome a. Need for endotracheal re-intubation within seven days of extubation.2. The secondary outcomes a. All-cause mortality before hospital discharge.b.All-cause mortality at 28 days.c.Failure of extubation (reintubation plus escalation or crossover to another NRS mode as rescue treatment).d.BPD (defined as need for oxygen or respiratory support at 36 weeks postmenstrual age).e. Composite outcome of death/BPD.